Summary: 1) BACKGROUND These studies investigate the impact of IL-1 blockade on a number of autoinflammatory diseases: NOMID, an acronym for "Neonatal Onset Multisystem Inflammatory Disease", is a rare chronic, systemic inflammatory disease leading to major disability in affected individuals. Affected patients present with an urticarial rash, fever, aseptic meningitis, papilledema, high frequency, sensorineural hearing loss, bony overgrowth especially of the knees, growth retardation and a significant number of patients are cognitively impaired. NOMID presents at the most severe end of a spectrum of diseases that are associated with mutations in CIAS1, a gene located on chromosome 1. The other two diseases being familial cold induced autoinflammatory syndrome (FCAS) or Muckle Wells syndrome (MWS). In contrast to FCAS and MWS, mutations in NOMD patients occur spontaneously and are present in about 50% of the patients. When we and one other group discovered that spontaneous missense mutations in the NACHT domain of CIAS1 are the cause of NOMID, the pathophysiological pathways associated with molecules containing the pyrin domain were just being associated with up regulation of caspase-1 or IL-1 converting enzyme (ICE) which, leads to increased cleavage of a pro-form of IL-1 into its active component. We subsequently hypothesized that IL-1 blockade may lead to clinical improvement in children with NOMID. A clinical trial using the IL-1 receptor antagonist Anakinra is currently conducted in children with NOMID. The other inflammatory conditions we study are as follows: FCAS is associated with a cold induced urticarial rash. In addition to the development of signs and symptoms of systemic inflammation, such as elevation of acute phase reactants, fever, joint pain, fatigue accompany the rash and resolves several hours after the cold exposure subsides. MWS is associated with a persistent urticarial rash that can not clearly be linked to a cold stimulus, the development of high frequency hearing loss, in some cases papilledema, and the development of amyloidosis. Still's disease is a rare arthritic syndrome without currently identified genetic associations. Still's disease presents with spiking fevers, evanescent salmon colored rash, arthritis, arthralgia and hepatosplenomegaly. Although Still?s disease typically first occurs during childhood, it can also have its onset in adulthood. FMF is a recessively inherited disease with a defect in the FMF gene that encodes for an abnormal protein called pyrin. FMF is characterized by episodes of fever, serositis, arthritis and in rare cases patients develop amyloidosis. This disease has been extensively been studied in Dr Daniel Kastner?s laboratory. Those projects are conducted in collaboration with his group. The gene that is mutated in the CIAS1 associated diseases encodes a protein, cryopyrin that has similarities in structure and function with pyrin the protein mutated in FMF. Both mutated proteins are associated with up-regulation of IL-1 production in vitro and in vivo. This has formed the rationale to develop a treatment approach targeting the IL-1 pathway as outlined above. 2) OBJECTIVE OF PRESENT STUDIES: a. the first study conducted in children and adults with NOMID evaluates the impact of IL-1 blockade with the FDA approved IL-1 receptor antagonist anakinra on the clinical signs and symptoms and laboratory markers of inflammation. Anakinra is given daily by subcutaneous injections. This study has completed recruitment. b. a second study is imitated to evaluate the impact of a new therapeutic agent, IL-1 TRAP with a longer halflife than anakinra on the clinical signs and symptoms and laboratory measures of inflammation in adult patients with CIAS1 diseases (NOMID, MWS or FCAS) and to test the impact of IL-1blockade in two other inflammatory diseases (adult onset Still?s disease and colchizine resistant, mutation proven FMF 3) RESULTS DURING THE PAST YEAR AND ONGOING INITIATIVES a. The anakinra study completed recruitment and all patients completed a one year evaluation. All 18 patients had remarkable clinical and laboratory responses to anakinra. In 15 of those patients laboratory markers of inflammation (including the erythrocyte sedimentation rate, the C reactive protein and the serum amyloid A protein level) completely normalized and clinical signs and symptoms disappeared or improved markedly. During a flare period when drug was withheld, all 11 patients who underwent this flare period developed rash, joint pain, headaches fevers and other clinical signs and symptoms that were present before their disease was treated with anakinra. In all patients laboratory markers of inflammation increased significantly during the flare period. Reinstitution of therapy produced the same immediate responses to anakinra as was seen with the first administration. We are enrolling a small cohort of children under the age of 2 to evaluate if early administration can prevent cognitive as well as hearing and vision impairment to occur. b. We have recruited 6 patients under this protocol. All patients with FCAS had significnat clinical and laboratory improvement of their disease. One patient with Still's disease was enrolled who had a partial response to IL-1 TRAP. 4) CONCLUSIONS AND SIGNIFICANCE a. As we hypothesized in the anakinra trial, IL-1 overproduction/activation as a result of de novo mutations in CIAS1 in children with NOMID seems to be the major pathophysiologic pathway promoting inflammation in children with NOMID. Blockade of IL-1 with the IL-1 receptor antagonist anakinra produces effective, almost instant relief from the clinical signs and symptoms. In addition ocular and auditory signs and symptoms have stabilized over the period of observation. We also have evidence that a number of the CNS manifestations of the disease (hearing loss, vision loss due to optic nerve edema and optic nerve atrophy and leptomeningitis) are inflammatory in nature. We are currently investigating if long term IL-1 blockade will prevent progression or even prevent the development of those symptoms. b. The IL-1 TRAP study indicates, significant relief and improvement in patients with FCAS, the drug is longer acting agent holds promise to be a more convenient agent, that can be administered weekly. Subsequently, administration of IL-1 TRAP to patients with two other autoinflammatory diseases, adult Still?s disease and FMF will delineate the impact of IL-1 blockade in these patients and may possibly point us to the important pathopysiologic pathways leading to disease expression in both diseases.